M2 Macrophage/Microglial Cells Induce Activation of Stat3 in Primary Central Nervous System Lymphoma
M2 Macrophage/Microglial Cells Induce Activation of Stat3 in Primary Central Nervous System Lymphoma
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DOI：
10.3960/jslrt.51.93
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发表时间：
2011-11-01
影响因子：
1.5
通讯作者：
Takeya, Motohiro
中科院分区：
文献类型：
--
作者：
Komohara, Yoshihiro;Horlad, Hasita;Takeya, Motohiro
原发性中枢神经系统淋巴瘤(PCNSL)是最具侵袭性的恶性淋巴瘤之一，中位生存期不到20-40个月。在过去的十年中，人们对信号转导和转录激活因子3(STAT3)的兴趣与日俱增，因为STAT3的激活被发现通过诱导血管生成、免疫抑制和转移而促进肿瘤的进展。我们先前证明了肿瘤细胞中STAT3的激活与浸润性抗炎(M2)巨噬细胞之间存在显著的相关性。在这里，我们重点研究了PCNSL细胞中浸润性巨噬细胞/小胶质细胞的表型和STAT3的激活。并探讨STAT3活化或M2巨噬细胞密度与患者预后的关系。我们用43例患者的石蜡包埋标本进行CD68、CD163、CD204和pStat3的免疫组织化学染色。CD163和CD204可作为M2表型的标记。CD68(+)巨噬细胞在所有标本中均有致密的浸润。CD163(+)和CD204(+)M2巨噬细胞/小胶质细胞分别高表达29例和25例。肿瘤组织中CD163(+)巨噬细胞/小胶质细胞密度较高者，淋巴瘤细胞中STAT3活性增强。体外共培养实验研究了巨噬细胞和淋巴瘤细胞之间的细胞间相互作用，发现淋巴瘤细胞中的STAT3在与巨噬细胞共培养时被强烈激活。CD68(+)、CD163(+)、CD204(+)肿瘤相关巨噬细胞/小胶质细胞(TAMs)数量及STAT3活化与预后无关。然而，由于STAT3参与了几种恶性肿瘤的发生发展，我们目前发现M2巨噬细胞/小胶质细胞与淋巴瘤细胞诱导的STAT3激活的细胞-细胞相互作用可能为PCNSL的发病机制提供新的见解。
Primary central nervous system lymphoma (PCNSL) is one of the most aggressive malignant lymphomas with a median survival of less than 20 similar to 40 months. Interest in signal transducer and activator of transcription 3 (Stat3) has increased during the past decade because Stat3 activation was found to contribute to tumor progression by inducing angiogenesis, immunosuppression, and metastasis. We previously demonstrated a significant correlation between Stat3 activation in tumor cells and infiltrating anti-inflammatory (M2) macrophages. Here, we focused on the phenotypes of infiltrating macrophages/microglial cells and Stat3 activation in PCNSL cells. The correlation of Stat3 activation or density of M2 macrophage infiltration with patient prognosis was also evaluated. We performed immunostaining for CD68, CD163, CD204, and pStat3 using paraffin-embedded PCNSL specimens obtained from 43 patients. CD163 and CD204 served as markers of the M2 phenotype. Dense infiltration of CD68(+) macrophages was found in all samples. High numbers of CD163(+) and CD204(+) M2 macrophages/microglial cells were observed in 29 and 25 cases, respectively. Stat3 activation in lymphoma cells was enhanced in the patients who showed denser infiltration of CD163(+) macrophages/microglial cells in tumor tissues. In vitro co-culture experiment to investigate cell-cell interactions between macrophages and lymphoma cells found that Stat3 in lymphoma cells was strongly activated by co-culture with macrophages. Numbers of CD68(+), CD163(+), and CD204(+) tumor-associated macrophages/microglial cells (TAMs) and Stat3 activation in lymphoma cells were not correlated with prognosis. However, because Stat3 involvement in tumor development was demonstrated in several malignant tumors, our present finding that cell-cell interactions of M2 macrophage/microglial cells with lymphoma cells induced Stat3 activation may provide novel insights into PCNSL pathogenesis.